Most Genetic Epidemiology Branch investigations evaluate the contributions of host susceptibility and environmental exposure in the development of cancer. In family studies, the host susceptibility measure is frequently an alteration in specific gene(s). Although two genes associated with melanoma susceptibility have been identified (CDKN2A and CDK4), alterations in these genes are found in only a small percentage of melanoma-prone families. The search for other genes continues in collaboration with an international consortium. Seven North American families with the V126D mutation, a common mutation of CDKN2A, had halotypes consistent with a common founder. The mutation appears to have arisen 34-52 generations ago, but the location where it arose is unknown. The gene covariate interaction between dysplastic nevi and melanoma was explored in 20 American melanoma-prone families, 13 of which had CDKN2A mutations. Dysplastic nevi, total nevi, or both were important covariates, but sun exposure was not. The effect of dysplastic nevi appeared greater in families without CDKN2A mutations. The study of familial chordoma, a rare, low-grade, malignant bone tumor derived from remnants of the notochord, was expanded to include two new families. Based on these families, multipoint analyses of affecteds only revealed a maximum LOD score of 4.78 at marker D7S500, with a 2-LOD support interval from marker D7S512 to marker D7S684. Attempts to identify the gene continue. The study of chronic lymphocytic leukemia was also expanded by use of a newsletter and a website. A genome-wide search for susceptibility genes is in progress. Other laboratory investigations include characterization of protein expression of candidate loci, cell surface marker analysis, characterization of telomerase activity in tumor cells, and analysis of expressed immunoglobulin heavy chains. A new study of Waldenstrom's macroglobulinemia was also initiated and is currently in the field phase.